The battle against ageing

“I have a lifetime appointment and I intend to serve it. I expect to die at 110, shot by a jealous husband,” the late US Supreme Court Justice Thurgood Marshall – civil rights champion and the first African-American to sit on the US’ highest court – once said in response to questions about his retirement. He finally stepped down in 1991, citing old age and medical problems for his decision. Less than two years later, he died of heart failure.

Marshall’s words and fate perfectly capture the common aspiration we all have for a long, lively, and productive life while making every effort to escape the inevitable – the inherent limits and progressive deterioration of the human body.

History is rich with extravagant and doomed attempts at immortality and rejuvenation.

In order to preserve their youthful skin, legend has it that Cleopatra used to bathe in donkey milk while Countess Elizabeth Bathory preferred the blood of virgins.

In the 16^th century, rumours that a miraculous spring could rejuvenate those who drank from it might have provided the Spanish explorer Juan Ponce de León with a powerful incentive to continue his explorations around the Florida coast.

Although no fountain of youth has yet been found, over the last decades, medical researchers studying different aspects of the ageing process have started to untangle some of its key biological processes. With each new discovery, we add another small piece to a very complex jigsaw, so much so that a treatment to slow ageing no longer belongs in the realm of science fiction but might actually be in the making.

The ambition is not so much eternal life but improving the quality of life, to identify those key mechanisms underpinning the ageing process and to hinder them and, by doing so, hopefully set off a chain reaction that will keep us healthy until old age by using the body’s own ability to heal itself.

“The goal of the research on ageing is not to elongate life but healthspan,” Dr Nir Barzilai, one of the key researchers in the field, told Global Health and Travel. “This would be beneficial not only for individuals but for societies as well because it would help reduce the huge costs of treating elderly people.”

Unleashing the power of cellular regeneration

For Drs Irina and Michael Conboy, the quest for an anti-ageing treatment started with blood.

During their postdoctoral research at Stanford University in the early 2000s, the couple was looking for a unifying principle to explain the complexities of the ageing process when they hypothesised that the answer could be flowing through our arteries and veins.

“The entire body gets old, it’s not like you have healthy and young eyes but old ears. And blood is what connects all our organs together, hence it may have something to do with what makes us old,” the researchers, currently working at the University of California, Berkeley, told Global Health and Travel. 

The idea was not that far-fetched given that previous experiments had shown that old mice stitched to younger ones to create a shared circulatory system – a state called parabiosis – improved their bone density and lengthened their lifespan.

Together with other researchers, they set up a similar study where old mice were joined to much younger ones and subsequently injured to monitor their ability to heal. “Our goal was to see whether ageing of cells and tissues is set in stone or is more dynamic and can be reversed,” they said.

The results, published on Nature in 2005, were nothing short of miraculous.

After just one month, old mice were healing as fast as young ones normally do. Their increased rate of cell proliferation led to better muscle, brain, and liver tissue repair.  

“This was proof of concept for tissue rejuvenation,” they said. “The take-home message was that age is just a number and it can be reversed or accelerated.”

Unfortunately, the results were grossly misinterpreted, they lamented, with many jumping to the wrong conclusion that young blood is a sort of secret elixir of life. Emblematic of this misinterpretation are the commercial enterprises that have sprung up to cash in on the supposed benefits of young blood transfusion.

One seminal event was held in February 2018 at a Florida symposium on ageing, not too far from where Juan Ponce de León was believed to have been searching for the fountain of youth. There, a crowd of baby boomers were urged to take action against their looming death by paying to enrol in a clinical trial testing the effects of young blood transfusion, according to STAT.

“We’re saying that we will defy ageing,” Dr Dipnarine Maharaj, the man in charge of running the trial in his private practice, told the crowd.

Even more worrying, Ambrosia, a start-up selling blood transfusions for US$8,000 per litre, is already up and running in five cities across the US. Although the company conducted a clinical trial in 2017 to test the efficacy of its services, it has yet to publish the results.

Touting the rejuvenating benefits of blood transfusion, however, is pure snake oil, according to Drs Irina and Michael Conboy. “There’s no scientific justification to do it, and there are serious risks involved, like infections and potential immune system rejection,” they said.

They contend that the infusion of young blood is not the right and practical way to unleash the anti-ageing effects observed in their research. Healthcare systems sometimes face blood supply shortages for standard transfusions, for example, so it’s unlikely they could have enough blood to treat the hundreds of millions patients who might benefit from an anti-ageing treatment.

In their view, developing a drug that pinpoints the components in our old blood that can forestall cell regeneration is the way towards a safe and sustainable anti-ageing approach.

“We’re working on finding what are metaphorically called ‘sunglasses’ – molecules that make us less sensitive to the effects of those substances that accumulate with ageing in the same way as sunglasses protect our eyes from sunlight,” they said.

Humans already have the potential to heal and renew their tissues until old age, thanks to stem cells that can divide and set off cell proliferation in every type of tissue whenever needed. In case of a muscle tear, for instance, stem cells can produce new muscle cells to replace the damaged ones.

However, this regenerative mechanism gets worn down over time, and increased levels of substances like the growth factor beta 1 (TGF-beta1) are considered one main reason behind it. TGF-beta 1 is a class of proteins that have a positive role during young age by regulating the formation of several types of tissue, such as bone, muscle and blood vessels, but its build-up hampers cell regeneration in old tissues.

In a study published in 2015, the Conboys and their research team showed that a drug interfering with TGF-beta1 was able to rejuvenate the brains and muscle of mice by increasing the activity of their stem cells.

“We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle,” said co-author David Schaffer, director of the Berkeley Stem Cell Center and a professor of chemical and biomolecular engineering, in a press release. “That is good news, because if every tissue had a different molecular mechanism for aging, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.”

The team’s working theory is that ageing is, in part, due to the inability of old stem cells to regenerate because of chemicals that accumulate in the body over the years and inhibit their regenerative function. With TGF-beta1 being just one of many factors influencing stem cell activity, the next step is to act on the others to set off a comprehensive process of rejuvenation in multiple aged tissues.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Dr Irina Conboy said in a press release.

Their hope is to design a human clinical trial that can demonstrate that drugs acting on ageing pathways will prevent or delay a host of conditions associated with old age, thus making people healthy for a longer time.

Metformin: From diabetes to anti-ageing drug?

Dr Nir Barzilai couldn’t reconcile his elderly grandfather’s tales of bravery during the war with his old and increasingly weak body.

“There’s no way this guy did what he says he did,” he kept thinking.

This got him incredibly curious about how and why humans age, setting him on a path to become the director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York.

To find clues about why a small number of people reach very old age without serious health problems while many others are plagued by diseases at a much younger age, Dr Barzilai analysed the genetic make-up of more than 500 healthy people between the ages of 95 and 112, revealing some genes that offer protection against age-related conditions.

“We’ve found lots of genetic characteristics associated with longevity, such as variations in the APOC-3 and CETP genes that lead to higher levels of good cholesterol [high-density lipoprotein cholesterol] while lowering the amount of triglycerides, but it’s not clear whether this is the reason behind the participant’s longevity,” he told Global Health and Travel.

While good cholesterol can lower the risk of heart disease, high levels of triglycerides have the opposite effect. Pharmaceutical companies are already testing drugs that mimic the effects of those genetic variations as a treatment for cardiovascular disease.

However, Dr Barzilai’s most ambitious undertaking, one that could lead to a paradigm shift in medical care, is to demonstrate that a common drug used to treat type 2 diabetes, whose risk increases as we age, can be repurposed as a preventive treatment for major chronic diseases.

In addition to its ability to regulate blood sugar levels in diabetics, the drug metformin has also shown a series of other health benefits across the board – this is why Dr Barzilai is betting hard on the chemical. “The only human clinical studies that have in part proven a potential treatment for ageing are those on metformin, which I think can really target ageing more than anything else,” he said.

In a US study of 3,000 participants at risk of developing type 2 diabetes, metformin reduced the chances of developing the condition by 31 percent compared to a placebo, or dummy pill. Those who took it saw improvements in cardiovascular disease risk factors as well. In a UK study, patients with type 2 diabetes on metformin experienced a 42 percent reduction in diabetes-related death and a 36 percent decrease in mortality from any cause.

Other studies have unearthed an association between metformin and a decrease in cancer risk, better cognitive function, and even reduced mortality in some diabetics compared to people without diabetes. This doesn’t mean that metformin can prevent cancer and cognitive diseases or extend lifespan, but it explains why many researchers are excited about the drug.

“If we take all of this together, you can see there’s a lot of evidence from human studies that metformin affects not only one disease but several, as well as mortality,” Dr Barzilai said. “Metformin is a cheap, generic drug. What we’re doing is trying to repurpose it to target ageing, and we’re going to show it by targeting not one disease, which is already done, but a composite of diseases.”

It’s still not clear why metformin might have rejuvenating effects, but one theory is that it helps reduce inflammation as well as oxidative stress, two major contributors to cell damage and many conditions typical of old age. This uncertainty invites more research on the drug’s mechanism of action and long-term effects on human healthspan. 

One problem hampering the development of anti-ageing medications, however, is that the multiple processes of deterioration we commonly call ageing are not considered a standard disease with clear-cut symptoms. Therefore, there’s no rationale for doctors to prescribe anti-ageing drugs or for insurers to reimburse them. With no financial incentive, explained Dr Barzilai, pharma companies have no interest in entering the fray.

The study on metformin Dr Barzilai is about to launch might change that.  

TAME (Targeting Ageing with Metformin) aims to study about 3,000 random people aged 65 to 80 to see whether metformin is able to interfere with ageing by having a positive effect on the risk of several conditions like heart and cognitive diseases as well as on mortality. The US Food and Drug Administration (FDA) has already greenlighted the effort, a major win considering that ageing is not classified as a disease by drug regulators.

“This is the first study on ageing designed with the advice of the FDA, so our purpose is also to change the culture around the research on ageing, otherwise there’ll be no development,” he said. “If the study succeeds, we’ll have demonstrated that ageing can be the target of medical intervention.”

Telomere length: a yardstick for cellular ageing

A common notion in medical science is that our hereditary characteristics, or DNA, influence almost every aspect of our health. It’s no surprise, then, that they’re now regarded as a major factor in how we age.

Specific gene types are associated with increased risk of cancer, heart disease, and other ailments. Other genes and mutations may offer protection instead, such as a variant of the PCSK9 gene that leads to very low blood cholesterol levels. Risk for heart disease rises with elevated “bad” cholesterol levels.

At the end of chromosomes, the structures containing the complete DNA of each cell, are telomeres, a sequence of proteins that act as a buffer to protect genetic material and the darling of anti-ageing researchers because of their supposed role in the ageing process.

“Telomeres throughout the body shorten as we age, and this underlying mechanism contributes to most diseases of ageing,” Elizabeth Blackburn and Elissa Epel, Professor of Biology and Physiology and Professor of Psychiatry, respecitvely, at the University of California, wrote in their book The Telomere Effect. “Telomeres explain how we run out of the ability to replenish tissue. There are other ways cells become dysfunctional or die early, and there are other factors that contribute to human ageing. But telomere attrition is a clear and an early contributor to the ageing process.”

In the course of our lives, some cells in the body reach a point where they’re not able to divide anymore, a state of affairs called senescence, which produces molecules that have both positive effects, such as promoting tissue repair, and negative ones, such as causing chronic inflammation, a risk factor for many diseases associated with ageing, like heart disease, diabetes, and arthritis.

Although senescent cells stop dividing to prevent cancer, which is characterised by uncontrolled cell growth, Dr Judith Campisi of the Buck Institute for Research on Aging in California discovered that in old people senescent cells experience DNA damage and genetic mutations that might develop into cancer. While senescent cells are rare in young people, they accumulate with age, possibly because the immune system is not able to clear them as quickly as before, leading to overall deterioration or what we commonly know as ageing, Dr Campisi told Global Health and Travel.     

“When too many of your cells are senescent, your body’s tissues start to age. For example, when you have too many senescent cells in the walls of your blood vessels, your arteries stiffen and you’re more likely to have a heart attack,” wrote the University of California’s professors.

Though other stresses on normal cells can make them senescent, extremely short telomeres are a main culprit. The researchers point to an array of studies that have shown a link between short telomeres and a host of conditions, like heart and cognitive problems, pulmonary diseases, diabetes, and mental stress (depression in particular). In some cases, short telomeres can be the predictor of early mortality. While at the opposite side of the spectrum, people with long telomeres tend to stay healthy longer.

Although telomere length is affected by genes, people have some degree of control over how long or short their telomeres are.

“The foods you eat, your response to emotional challenges, the amount of exercise you get, whether you were exposed to childhood stress, and even the level of trust and safety in your neighbourhood — all of these factors and more appear to influence your telomeres and can prevent premature ageing at the cellular level. In short, one of the keys to a long healthspan is simply doing your part to foster healthy cells renewal,” they wrote.

Apart from reducing inflammation and improving well-being, mind-body techniques like meditation, tai chi, and yoga have shown the capacity to elongate telomeres, which similarly “appear to respond powerfully to many different types of exercise,” with no need of extreme workout regimens. One study suggested that the more categories of exercise people engage in the greater their telomere length.

While being overweight is not necessarily an enemy of telomeres, the professors stressed that belly fat is. The way to slash it is a nutritious diet of whole foods, such as fresh vegetables, fruits, whole grains, nuts, legumes, and omega-3 fatty acids.

Dr Campisi agrees that engaging in those lifestyles will make people healthier and probably expand their healthspan, but she doubts telomeres are the magic bullet that can make the difference against ageing. “Telomeres are one important indicator of the overall ageing process, but having long telomeres doesn’t necessarily give us healthier tissues,” she told Global Health and Travel.

A new anti-ageing medication counteracting the deleterious effects of senescence might be a real game changer, according to her, with senolytic drugs, a class of medications able to kill senescent cells, being some of the most promising candidates.

“Senolytic drugs might be the most appropriate drugs to tackle senescence because they eliminate just a portion of senescent cells, thus preventing them from causing damage but possibly preserving their positive tissue repair functions.”

She cofounded a company called Unity Biotechnology that last July started a human trial to study the effects of a senolytic drug in treating osteoarthritis of the knee.

“The longterm goal is to prove that bringing senescent cells to youthful levels provides benefits across the board and is one way towards a longer healthspan,” she said.

How can I cope with ageing right now?

First things first: you should avoid dubious treatments that promise to set the clock back.

This is because there’s still no medication, supplement, hormone, blood injection, or secret concoction that can forestall ageing, let alone reverse it.

Any supplements or pills that aim to lengthen telomeres or increase telomerase, the enzyme in charge of producing telomere DNA, are particularly dangerous because they can increase cancer risk, wrote Professors Blackburn and Epel.

“We need our good Dr Jekyll telomerase to stay healthy, but if you get too much of it in the wrong cells at the wrong time, telomerase takes on its Mr Hyde persona to fuel the kind of uncontrolled cell growth that is a hallmark of cancer.”

Until one of the promising anti-ageing drugs under development proves to be effective, the best strategy is to eat wholesome food, exercise in moderation, and keep our stress levels under check – activities that make us healthier with no increase in cancer risk.

Maybe this won’t buy you more time, but it will definitely help keep age-related conditions away for as long as possible.